Details for Patent: 5,223,261

Summary for Patent: 5,223,261

Title:	Transdermal estradiol delivery system
Abstract:	A pressure-sensitive adhesive sheet material for delivering estradiol to skin, the sheet material comprising a backing with a layer of a pressure-sensitive adhesive adjacent thereto, said pressure-sensitive adhesive layer comprising a pressure-sensitive adhesive polymer, two or more skin penetration-enhancing ingredients and estradiol. The sheet material is useful for systemic treatment of conditions associated with estradiol deficiency. Methods of using such adhesive sheet material are also described.
Inventor(s):	Gregory R. Nelson, Horst-Georg Zerbe, Cheryl L. Moore, Steven M. Wick
Assignee:	3M Innovative Properties Co
Application Number:	US07/815,908
Patent Claim Types: see list of patent claims	Use; Delivery;

United States Patent 5,223,261 (Estradiol Transdermal Adhesive Sheet): Claim Scope and US Patent Landscape

US Patent 5,223,261 claims pressure-sensitive adhesive (PSA) transdermal sheet materials that deliver estradiol through skin over prolonged periods, with a defined acrylic copolymer PSA architecture and a specific skin penetration enhancer system of isopropyl myristate + glyceryl monolaurate, optionally with ethyl oleate. The claim set is tightly focused on (1) polymer composition ranges, (2) estradiol loading ranges, (3) enhancer loading ranges and pairing logic, and (4) continuous transdermal delivery and adhesion behavior.

Important outcome for freedom-to-operate (FTO): the most enforceable claim elements are the combination of (a) the particular acrylic copolymer composition ranges, (b) estradiol concentration window, and (c) the specific penetration enhancer combination with stoichiometric constraints. Design-arounds that omit either the enhancer pairing or materially change the monomer composition ranges are most likely to reduce literal infringement risk.

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What is claimed in US 5,223,261 (estradiol PSA transdermal sheet) and what is the enforceable core?

Core claimed subject matter (Claim 1 / Claim 9 independent framework):
A transdermal adhesive-coated sheet comprising:

1. Flexible backing
2. Pressure-sensitive adhesive coating homogeneously mixed and contiguously adhered to one surface of the backing, containing:
   • (i) Acrylic copolymer with defined monomer composition ranges
   • (ii) Estradiol at defined wt% of adhesive coating
   • (iii) Skin penetration enhancer combination containing:
     • Isopropyl myristate: about 5 to 20 wt%
     • Glyceryl monolaurate: about 1 to 6 wt%
   • (iv) functional relationship: enhancer amounts are selected to enhance estradiol skin penetration versus the same coating without enhancers
3. Functional performance characterizations:
   • Over prolonged period it adheres suitably to skin
   • Provides substantially continuous transdermal delivery of estradiol at a therapeutically effective amount for treating estradiol deficiency conditions

What is the “enforceable core” in practical claim construction?

From the claim grammar, the enforceable combination is:

• The defined PSA copolymer architecture + estradiol loading + the specific enhancer pair with specified ranges
• plus the adhesive sheet’s performance properties (continuous delivery and adequate adhesion “over a prolonged period”).

If a competitor’s product uses a different enhancer system (even if it improves penetration), the claim likely fails the literal “skin penetration enhancer combination comprising isopropyl myristate and glyceryl monolaurate” element.

If a competitor uses the same enhancers but a materially different acrylic copolymer monomer ratio, the polymer composition limitation may defeat literal infringement.

If a competitor uses the same polymer and enhancers but estradiol loading outside the recited wt% range, literal infringement likely fails.

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What are the exact claim 1 composition ranges in US 5,223,261 (acrylic copolymer, estradiol, enhancers)?

Claim 1: adhesive-coated sheet material composition

(i) Acrylic copolymer (monomers by wt% of all monomers in said copolymer)

• About 91 to 98 wt%: hydrophobic acrylic or methacrylic acid ester of alkyl alcohol
  • alkyl alcohol: 4 to 10 carbon atoms
• 2 to 9 wt%: reinforcing monomer selected from:
  • acrylic acid
  • methacrylic acid
  • acrylic or methacrylic acid alkyl acrylate/methacrylate with 1 to 3 carbon atoms in alkyl group
  • acrylamide
  • methacrylamide
  • lower alkyl-substituted acrylamide
  • diacetone acrylamide
  • N-vinyl-2-pyrrolidone
  • vinyl ether
  • vinyl ester
  • substituted ethylene

(ii) Estradiol

• About 0.2 to 12 wt% of the adhesive coating

(iii) Skin penetration enhancer combination

• isopropyl myristate: about 5 to 20 wt%
• glyceryl monolaurate: about 1 to 6 wt%
• and “relative amounts being selected so as to enhance penetration” relative to coating lacking these enhancers

(iv) Performance

• suitable adhesion to skin over prolonged period
• substantially continuous transdermal delivery of estradiol at therapeutically effective dose for estradiol deficiency conditions

Claim 1: key “optionally expandable” limitation via dependent claims

Claim 1 itself does not require ethyl oleate. Ethyl oleate appears only in dependent Claim 7.

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How do claim 2 to claim 7 narrow the polymer and enhancer scope (and where is infringement likely strongest)?

Claim 2 (polymer narrower hydrophobic range)

• Acrylic copolymer comprises acrylic of methacrylic acid ester in amount about 94 to 98 wt%
  Compared with Claim 1’s 91 to 98 wt%, Claim 2 narrows the hydrophobic ester window.

Claim 3 (specific monomers: isooctyl acrylate + acrylamide)

• hydrophobic monomer: isooctyl acrylate
• reinforcing monomer: acrylamide

This is a classic “narrow species” sub-claim. Products whose PSA is built on different ester alkyls or different reinforcing monomers can avoid literal dependence on Claim 3, but they may still risk infringement of Claim 1 / Claim 2 depending on their monomer composition.

Claim 4 and Claim 5 (estradiol wt% sub-ranges)

• Claim 4: estradiol about 1 to 5 wt%
• Claim 5: estradiol about 2 to 3.5 wt%

These are tighter loading windows than Claim 1’s 0.2 to 12 wt%.

Claim 6 (enhancer narrower windows)

• isopropyl myristate: about 5 to 15 wt%
• glyceryl monolaurate: about 2 to 4 wt%

Claim 7 (adds ethyl oleate, constrains total)

• ethyl oleate present at about 4 to 18 wt% (based on adhesive coating)
• total isopropyl myristate + ethyl oleate less than about 30 wt% (based on adhesive coating)

This creates another degree of freedom. A product could include ethyl oleate but still avoid dependent Claim 7 if it violates the “total isopropyl myristate and ethyl oleate < 30 wt%” constraint.

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What does US 5,223,261 claim on methods of treatment (claim 8) and how broad is it?

Claim 8

A method of treating estradiol deficiency conditions:

• applying the claimed adhesive-coated sheet (per Claim 1)
• adhered to skin of a mammal
• permitting systemic delivery of estradiol

Scope character: method claim is limited by the sheet composition defined in Claim 1. It is not a standalone “use estradiol transdermally” claim; it ties directly to the specific adhesive sheet composition with defined copolymer + estradiol + enhancer system.

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How does claim 9 change the PSA copolymer architecture compared with claim 1 (and what is the practical effect)?

Claim 9 is another independent adhesive-coated sheet formulation, with a materially different copolymer structure:

Claim 9 PSA copolymer composition

• About 60 to 80 wt% hydrophobic monomeric acrylic or methacrylic acid ester of alkyl alcohol (alkyl alcohol 4 to 10 carbon atoms)
• About 4 to 9 wt% reinforcing monomer selected from an overlapping list (acrylic acid/methacrylic acid, small alkyl acrylates/methacrylates, acrylamide derivatives, diacetone acrylamide, N-vinyl-2-pyrrolidone, etc.)
• About 15 to 35 wt% vinyl acetate in the copolymer

Estradiol and enhancer system appear as in Claim 1 (same wt% windows for estradiol, isopropyl myristate, glyceryl monolaurate, and “enhance penetration vs enhancer-free” functional language).

Practical effect

If a competitor uses a PSA copolymer that is not predominantly hydrophobic ester with low vinyl acetate (Claim 1’s architecture) but instead is within the vinyl acetate 15–35% range (Claim 9 architecture), they could fall under Claim 9 even if they miss Claim 1.

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What additional narrowing do claim 10 to claim 14 provide for claim 9-based formulations?

Claim 10 (species narrowing)

• hydrophobic ester: isooctyl acrylate
• reinforcing monomer: acrylamide

Claim 11 and claim 12 (estradiol loading windows)

• Claim 11: estradiol about 1 to 5 wt%
• Claim 12: estradiol about 2 to 3.5 wt%

Claim 13 (enhancer narrower windows)

• isopropyl myristate about 5 to 15 wt%
• glyceryl monolaurate about 2 to 4 wt%

Claim 14 (adds ethyl oleate and total constraint)

• ethyl oleate about 4 to 18 wt%
• total (isopropyl myristate + ethyl oleate) < about 30 wt%

As with Claim 7, the “total” constraint matters for literal infringement.

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What is claimed in claim 15 (method-of-treatment tied to claim 9)?

Claim 15

A method of treating estradiol deficiency by:

• applying and adhering the Claim 9 adhesive-coated sheet to mammal skin
• permitting systemic delivery of estradiol

This is the method counterpart tied to the Claim 9 formulation architecture (including vinyl acetate in the copolymer).

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How broad is the claim scope across chemical alternatives (monomer lists and enhancer pairing)?

Polymer reinforcing monomer is a closed genus list

Claim 1’s reinforcing monomer selection is restricted to an enumerated group. While it is broad in chemistry, it is still a defined list. A polymer using reinforcing monomers outside the enumerated set can reduce literal risk.

Alkyl acrylate/methacrylate hydrophobic ester window is defined by carbon count

The hydrophobic ester comes from alkyl alcohol containing 4 to 10 carbon atoms. Use of esters outside that alkyl chain length window can reduce literal infringement.

Enhancer system is limited by required co-presence

The claimed enhancer combination must comprise both:

• isopropyl myristate
• glyceryl monolaurate in recited wt% ranges. A formulation using either enhancer alone or a different glyceryl ester (or different lipid enhancer) can avoid this element.

Functional language (“enhances penetration compared to when free of enhancers”) is a comparative requirement

This is a built-in proof hook. If challenged, the patentee can argue performance via comparative penetration data; however, for infringement analysis the key is that the enhancer pair is present and within the recited ranges.

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What does the patent estate likely protect beyond these claims (continuations, related families, and later improvements)?

No additional claim text, priority details, family members, or related US continuations are provided in the input. Without those, a complete and accurate landscape across related applications cannot be produced.

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When does US 5,223,261 lose exclusivity (expiration and terminal disclaimer timing)?

No filing date, priority date, or patent term adjustment (PTA)/terminal disclaimer data is provided in the input. Without that, exclusivity timing cannot be stated precisely.

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What generic entry risks exist for estradiol transdermal PSA products under this patent?

Based strictly on the claim language, generic or follow-on entrants face the highest risk when their product matches all of the following simultaneously:

• PSA copolymer within one of the two architectures:
  • Claim 1: predominantly hydrophobic ester (91–98 wt%) with 2–9 wt% reinforcing monomer; or
  • Claim 9: hydrophobic ester 60–80 wt%, reinforcing monomer 4–9 wt%, and vinyl acetate 15–35 wt%
• Estradiol loading within 0.2–12 wt% (and particularly within narrower dependent ranges if asserted)
• Presence of both penetration enhancers in the specified wt% ranges:
  • isopropyl myristate 5–20 wt%
  • glyceryl monolaurate 1–6 wt%
• Performance assertions about prolonged adhesion and substantially continuous delivery are harder to “design around” because they are functional properties, but literal infringement still turns on whether the composition meets the claimed structure.

Lower risk scenarios (based on claim element deletion):

• Replace either isopropyl myristate or glyceryl monolaurate with a different enhancer
• Shift enhancer wt% outside the recited windows
• Shift polymer away from the claimed monomer composition ranges, especially vinyl acetate presence/absence and reinforcing monomer identity

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What other estradiol transdermal technologies likely fall outside the claim scope?

Based on the claim drafting style, products that are structurally different from “adhesive-coated sheet” PSA delivery systems may fall outside:

• membrane-and-reservoir systems with different penetration enhancer placements not in a PSA homogeneous mixture
• non-PSA transdermal platforms (sprays, gels, microneedle patches without a PSA sheet)
• formulations where estradiol is not homogeneously mixed in the PSA coating or where the required enhancer system is not in the PSA coating

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Key Takeaways

• US 5,223,261 is composition- and platform-limited: estradiol in a PSA transdermal adhesive sheet with a defined acrylic copolymer architecture and a defined isopropyl myristate + glyceryl monolaurate enhancer pair.
• The strongest literal infringement position is achieved by matching Claim 1 (predominantly hydrophobic ester PSA) or Claim 9 (vinyl acetate-bearing PSA), plus the estradiol wt% and enhancer wt% windows.
• Dependent claims 2–7 and 10–14 narrow species ranges (specific monomer selections, tighter estradiol and enhancer windows, and ethyl oleate inclusion with a total constraint).
• Method claims (8 and 15) track the corresponding sheet composition claims, so method infringement is tied to the formulation.

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FAQs

1) What monomer combinations are explicitly covered for the acrylic copolymer in US 5,223,261?

Claim 1 covers hydrophobic acrylic/methacrylic acid esters of alkyl alcohols with 4–10 carbons (91–98 wt%) plus a reinforcing monomer selected from a defined list at 2–9 wt%. Claim 9 requires hydrophobic ester 60–80 wt%, reinforcing monomer 4–9 wt%, and vinyl acetate 15–35 wt%. Dependent claims add species examples: isooctyl acrylate + acrylamide.

2) Does US 5,223,261 require ethyl oleate in the penetration enhancer system?

No. Ethyl oleate appears only in dependent Claims 7 and 14.

3) What happens if a formulation uses isopropyl myristate but not glyceryl monolaurate?

The claim requires the enhancer combination to comprise both isopropyl myristate and glyceryl monolaurate within defined wt% ranges. Omitting one can avoid the literal “skin penetration enhancer combination comprising…” element.

4) Are estradiol loading ranges flexible or rigid in the claims?

They are recited as wt% ranges (0.2–12 wt% in independent claims; narrower windows in dependent claims). Literal infringement depends on meeting those numeric windows.

5) What is the relationship between the adhesive sheet and the treatment method claims?

Claims 8 and 15 are method-of-treatment claims that require applying the corresponding claimed adhesive-coated sheet to mammal skin to permit systemic delivery.

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References

1. United States Patent 5,223,261.

Drugs Protected by US Patent 5,223,261

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,223,261

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0402407		97C0005	Belgium
Austria	109357
Australia	2097892
Australia	3280989
Australia	630347
Australia	651234
Canada	1338819